Solid pharmaceutical and vaccine dose

ABSTRACT

An elongate body for parenteral injection at low velocity from a device is described. The body has at least one pointed end and comprises at least one active material. In addition, the body has a compressive strength of greater than or equal to 5 Newton and the pointed end has an included angle of between about 10-50°. A solid vaccine formulation for needle-free parenteral delivery, methods for making the body, packaging of the body and use of the body, packaging and suitable delivery device are also described.

This application is continuation of U.S. application Ser. No. 14/095,101(pending), filed Dec. 3, 2013 (published as US 2014-0093553 A1), whichis a divisional of U.S. application Ser. No. 12/527,980 (abandoned),filed Aug. 20, 2009 (published as US-2010-0119570-A1), which is a U.S.national phase of International Application No. PCT/GB2008/000589, filed20 Feb. 2008, which designated the U.S. and claims priority to GB0703507.4, filed 22 Feb. 2007 and GB 0723310.9, filed 28 Nov. 2007, theentire contents of each of which is hereby incorporated by reference.

The present invention relates to an elongate body and solid formulationfor parenteral injection at low velocity from a device, which can beused with a needle-free injector. The body has at least one pointed endand comprises at least one active material, which can be a vaccine. Inaddition, the body has a compressive strength of greater than or equalto 5 Newton and the pointed end has an included angle of between about10-50°.

A vaccine is an antigenic preparation used to establish immunity to adisease. Vaccines can be prophylactic (e.g. to prevent or ameliorate theeffects of a future infection by any natural or “wild” pathogen), ortherapeutic (e.g. vaccines against cancer).

There are four types of traditional vaccines. Vaccines containing killedmicroorganisms are derived from previously virulent micro-organisms thathave been killed with chemicals or heat. Examples are vaccines againstflu, cholera, bubonic plague, and hepatitis A. Vaccines containing live,attenuated microorganisms are derived from live micro-organisms thathave been cultivated under conditions that disable their virulentproperties. They typically provoke more durable immunological responsesand are the preferred type for healthy adults. Examples include yellowfever, measles, rubella, and mumps. Toxoids are inactivated toxiccompounds from micro-organisms in cases where these (rather than themicro-organism itself) cause illness. Examples of toxoid-based vaccinesinclude tetanus and diphtheria. Rather than introducing an inactivatedor attenuated micro-organism to an immune system, a fragment of themicro-organism can create an immune response. Characteristic examplesinclude the subunit vaccine against HBV that is composed of only thesurface proteins of the virus (produced in yeast) and the virus-likeparticle (VLP) vaccine against human papillomavirus (HPV) that iscomposed of the viral major capsid protein.

A number of innovative vaccines are also in development and in use.Certain bacteria have polysaccharide outer coats that are poorlyimmunogenic. By linking these outer coats to proteins (e.g. toxins), theimmune system can be led to recognise the polysaccharide as if it were aprotein antigen. This approach is used in the Haemophilus influenzaetype B vaccine. Alternatively, by combining the physiology of onemicro-organism and the DNA of the other, immunity can be created againstdiseases that have complex infection processes. In recent years a newtype of vaccine, created from an infectious agent's DNA, called DNAvaccination, has been developed. This works by insertion (andexpression, triggering immune system recognition) into human or animalcells, of viral or bacterial DNA. Some cells of the immune system thatrecognise the proteins expressed will mount an attack against theseproteins and cells expressing them. Because these cells live for a verylong time, if the pathogen that normally expresses these proteins isencountered at a later time, they will be attacked instantly by theimmune system. One advantage of DNA vaccines is that they are very easyto produce and store.

The prophylactic use of vaccines has been practiced for many decades toprotect against a wide range of diseases. Some vaccination campaignshave been so successful that a number of diseases are now rare in manyparts of the world. Many new vaccines are in development for eithertherapeutic and/or prophylactic use.

Most vaccines must be administered via an injection, although a fewvaccines have been developed for oral or nasal administration.Injections have traditionally been administered with a needle andsyringe with the vaccine in a liquid form. This technique has a numbermajor drawbacks, in particular, needle phobia (reduced compliance),liquid formulation (stability and cold chain storage issues), and needledisposal (potential for cross contamination). Some vaccines are notsufficiently stable in a liquid form, even if they are refrigerated, andthese have to be kept as a powder. Prior to injection these powders mustbe reconstituted, adding further complexity to the process.

Micro-needle patches are in development for vaccinations. These havetiny microneedles which are either coated in antigen or which have tinyholes in them through which the antigen can be pushed. The microneedlesare inserted into the outer layers of the skin to benefit from theenhanced immunogenicity in the skin.

Vaccines for nasal administration have also been developed, to benefitfrom the delivery to nasal mucosa. However, these systems are veryexpensive to produce. A small number of oral vaccines are commerciallyavailable and other routes of administration are in development butthese are unlikely to be in routine use for many years, if at all.

There are many different routes for delivering therapeutic compositions.In general, oral administration is the preferred route since many drugsubstances are readily absorbed in the gastrointestinal tract. It isalso a form of administration that is well accepted by patients andusually results in good patient compliance. However, not all drugsubstances can be formulated for oral delivery and such anadministrative route does not always provide the optimal bioavailabilityof a drug.

One route of administration that circumvents the gastrointestinal tractis referred to as parenteral administration and it is commonly the routeof choice for drugs that are degraded or are erratically or unreliablyabsorbed when administered orally.

The skin is one of the more efficient routes for parenteral delivery ofa therapeutic compound and such administration is most commonlyundertaken using a needle and syringe as a delivery system, with thetherapeutic compound in a liquid form. The needle and syringe deliverysystem has a number of drawbacks, including the pain and fear associatedwith needles, the requirement for a liquid formulation and the sharphazard created by using and disposing of needles.

Needleless drag delivery systems can be used for injecting liquidsthrough the skin. Such a delivery method is typically achieved bycreating a very fine, high velocity liquid jet that creates its own holethrough the skin. There are however a number of problems with such amethod, including splash back.

With both forms of liquid delivery, relatively large volumes of liquidare injected which, because the liquid is incompressible, have to tearthe tissue apart in order to be accommodated. In addition, not alltherapeutic compounds have a good solubility in water, resulting in therequirement to add potentially toxic additives or surfactants to thesolution. In addition, an aqueous solution of any given therapeutic istypically chemically less stable than a dry formulation of the samecompound. An aqueous solution is prone to microbial contamination andneeds to be sterilized using heat, radiation, filtration or chemicalmeans. Furthermore, the shelf life of an aqueous formulation mustusually be enhanced either by the addition of preservatives,stabilizers, anti-oxidants and the like or by special storage conditionsat low temperatures to avoid chemical or microbial breakdown of theactive ingredients.

Drug injection through the skin does not have to be achieved with thedrug in a standard liquid form. Solid form drugs have been successfullyadministered with the PowderJect system, which uses a compressed gassource to accelerate powdered drugs to a velocity at which the outerlayers of the skin can be penetrated. Such a system typically usespowdered drug particles having a diameter of less than 100 microns andrequires a velocity of several hundred meters per second to penetratehuman tissue. However, the system has its own inherent problems, such ascontrolled delivery and precise penetration depth. In parenteralinjection, it is important to deliver the therapeutic compound to thecorrect tissue since drugs that do not penetrate the cutis are not takenup by the body, some drugs must reach the muscular tissue or be taken upinto the blood stream via the subcutis within a predetermined timeframe. Energising means used to inject powder particles may includecompressed gas and explosives, such as propane, gasoline or gunpowder.Such explosive means provide the administration apparatus with their owninherent potential danger.

It has also been shown that solid rods or splinters of a therapeuticcompound can be pushed, at a relatively low velocity, into the skinwithout the requirement for a needle, although these are moretraditionally delivered as implants.

EP 0139286 (Sumitomo Chemical Co Limited) discloses sustained-releasepreparations in the form of needle- or bar-like shapes which comprise anactive ingredient and a pharmaceutically acceptable biodegradablecarrier. The sustained release preparation can be administered to thebody by injection by pushing it through a hollow needle or byimplantation.

U.S. Pat. Nos. 5,542,920, 6,117,443 and 6,120,786 (Cherif Cheikh)disclose needleless parenteral introduction devices and medicaments inthe form of a solid needle having a pointed end and sufficientstructural integrity to penetrate the skin. The needles are less than 2mm, preferably 0.2 to 0.8 mm, in diameter and 10 to 30 mm in length.

U.S. Pat. No. 6,102,896 (Roser) is primarily directed to a disposableinjector device for injecting controlled release water soluble glassneedles. However, it also recognises that these glass needles, which areabout 1 mm in diameter by 10 mm in length and contain a medicament, mayalso be used as pioneer projectiles to produce a low resistance pathwaythrough the tissue along which a liquid suspension (exemplified as adrug in a suspension of PFC fluid) can flow. This document appears thefirst and only document to recognise that a dissolvable pioneerprojectile may be used to enable the introduction of a medicament.However, it fails to recognise that it may be used as a generaltechnique for introducing medicaments in other forms.

WO 03/23773 (Caretek Medical Limited) relates to a method of deliveringa solid therapeutic formulation in which a glassy projectile ispropelled at low velocity from a device. The projectile creates apassage in the skin that accommodates a therapeutic composition thatfollows behind, independently of the projectile.

WO 94/22423 (Bukh Meditec A/S) discloses a solid pharmaceuticalcomposition in the form of a needle-shaped body that must have a shapeand strength to enable it to penetrate unbroken skin causing as littletissue damage as possible. To achieve this, the body is an elongatedshape with a pointed end that is created by a diagonal cut. The strengthis provided by the composition which includes gelatin as a basesubstance and crystalline or caramelised carbohydrate. Because the bodyis essentially pushed into the skin from a static start without priorpropulsion, the body must have a minimum compressive strength of 15,000lbs/in² (approximately 100N/mm²). For a rod having a typical diameter of0.85 mm, this would result in a crash strength of approx 56 Newton.

WO 94/22423 also discloses a process for preparing the formulationcomprising i) mixing a polymer and optionally a filler with an activedrug substance, ii) extruding the mixture containing the active drugthrough a die to form an elongate body, iii) drying the body, and iv)cutting the body to form a pointed end.

WO 00/62759 (Novo Nordisk) describes a solid pharmaceutical compositionfor parenteral injection comprising at least one therapeutic agent and acarbohydrate binder in an amount of at least 0.5% by weight, in whichthe carbohydrate binder forms an amorphous matrix. The addition of anon-crystallisation agent is optional. The applicants of WO 00/62759have found that the use of an amorphous matrix allows the composition tohave a lower compressive strength, typically at least 5 Newton andpreferably 10 to 40 Newton. However, standard extrusion of thecomposition tends to incorporate air into the composition resulting in acomposition that is not sufficiently strong to penetrate tissue and mustbe injected by a hypodermic needle, a trocar or similar means.Therefore, strength is imparted to the composition by injectionmoulding.

The Applicant has identified that there is a need for an improved solidcomposition for needleless parenteral delivery. In particular, theApplicant has recognised that it is the shape of the composition,especially the geometry of a pointed end, that has a bearing on theforce required to enable the composition to penetrate the skin causingminimal pain and damage. The Applicant has also found that a combinationof formulation strength and the velocity of the formulation as thecomposition strikes the skin provides the optimal design for effectivepenetration. Indeed, providing the composition with some velocity beforeit strikes the skin allows the composition to have a lower inherentstrength. This is in contrast to WO 94/22423 which requires a very highcompressive strength (approximately 56 Newton) because little or novelocity is imparted to the composition before it strikes the skin.

Stability of vaccines is one of the biggest issues within the vaccineindustry. Large quantities of vaccines are wasted every year due tobreakdowns in the cold chain. These issues are particularly acute indeveloping countries. Thus, the development of vaccines that do notrequire refrigeration would be a huge boost to the vaccine industry.Thus, the development of vaccines that do not require refrigerationwould be a huge boost to the vaccine industry. In addition, manyvaccines are unstable and so they are stored in a solid form, typicallyas a lyophilised powder, which is more stable than a liquid. However,even the solid forms currently available require refrigeration.Currently, vaccines in solid formulations need to be reconstituted priorto injection with a needle and syringe. If the vaccine can bemanufactured and stored in a solid dosage form and also administered inthis same form then it has the benefits of a more stable formulationwithout the complications of the reconstitution steps. In addition tothe added complications of reconstitution there are the added costs ofrequiring not just the vaccine but also a separate vial of diluent suchas water.

Also, many vaccines do not build up the required immune response after asingle administration and a prime administration followed by either oneor two ‘boost’ administrations maybe required to achieve sufficientimmunisation. Different antigens have different treatment regimes butthe first boost injection is typically administered two to four weeksafter the prime and a second boost may be given a further one to sixmonths later. Some vaccines (e.g. for influenza) do not provide lastingprotection and so a patient may need to be vaccinated every year. Inaddition, some vaccines (e.g. for influenza) need to be changedregularly (annually for flu) to ensure that protection is being givenagainst appropriate strains.

With some antigens, the immune response can also be enhanced by addingadjuvants to the formulations. The most common adjuvant is alum(aluminium hydroxide) which is insoluble, although other adjuvants arein development or are already on the market.

It has been demonstrated that the skin is very immunogenic and so, if anintradermal injection can be made, it should result in an enhancedimmune response. This offers the potential to use lower doses of antigento achieve the required immune response. Making a true intradermalinjection with a needle and syringe is very difficult and thereforeinjections are normally given into either the muscle or subcutaneoustissue.

Liquid jet injectors have been developed for mass vaccination campaigns.These technologies still have all the issues associated with liquidformulations and tend to require expensive or complicated power sources.Confidence was lost in this type of system in the past whencross-contamination of diseases was seen in patients due to thevaccination procedure.

The PowderJect technology (now owned by Pfizer) fires powders into theskin which either contain the antigen or which have the antigen coatedonto them. The system has been most successful for the delivery of DNAvaccines which are coated onto gold carrier particles. It is believedthat the gold particles are small enough to be delivered into the cellsof the dermis and it is the intracellular administration that providesthe enhanced immunogenicity. However, the system has its own inherentproblems, such as controlled delivery and precise penetration depth indifferent skin types and locations on the body. Energising means used toinject powder particles include compressed gas and explosives, such ashelium, propane, gasoline or gunpowder. Such explosive means provide theadministration apparatus with their own inherent potential danger. Thesedevices are also complicated and therefore expensive.

The vaccine industry can be split into at least three distinct areas:

-   -   Industrialised countries    -   Developing countries    -   Biodefence

Each of these three areas has particular needs and priorities as shownin Table 1. The table illustrates the relative importance of differentfeatures in the three areas of the vaccine industry. The higher thenumber, the more important the feature is for that territory.

TABLE 1 Data from Gideon Kersten, Needle-free & Autoinjectors,Management Forum, 22-23 Mar. 2007, London Emergency use DevelopingIndustrialised (biodefence, Key Features countries countries pandemic)Cheap 5 2 3 Stable 4 2 4 Easy to use 4 1 4 “Pain-free”/Needle 1 5 1phobia No adverse effects 1 4 1 No cross-contamination 5 4 4 Quick todistribute 2 3 5

Industrialised Countries: Childhood vaccination is the most common typeof vaccination in the industrialised world but there is also a bigmarket for travel vaccines. The main issue for vaccinations inindustrialised countries is compliance. Patients must believe that thevaccinations are safe and, if they can be administered in a more‘patient-friendly’ manner, more people will be vaccinated. In 1998 therewere reports in the UK that the combined measles, mumps and rubellavaccinations in babies might be causing autism in some of the children.These reports led to many children not being vaccinated which in turnled to increased outbreaks of measles in the UK. Many new vaccines arein development and these may initially only be marketed inindustrialised countries due to cost constraints. These include vaccinesagainst infections such as human papillomavirus (HPV).

Developing Countries: The main issues for vaccination programmes indeveloping countries are 1) to avoid needles, which are routinely reusedand therefore cause the spread of blood-borne diseases such as hepatitisB and HIV, and 2) to have more stable vaccines that do not rely onrefrigeration. Maintaining cold chain storage in industrialisedcountries is challenging enough without having to keep materials cold inparts of the world where ambient temperatures can be high and that oftendo not have reliable electricity supplies. Reports state that up to 50%of vaccines have to be thrown away due to breakdown in cold chainstorage. In addition to the two main criteria set out above, vaccinationprogrammes in developing countries are often funded by charities and soonly low cost technologies can be employed in order to vaccinate as manypeople as possible.

Emergency Use: Following the terrorist attacks in America in 2001, theUS Government started to stockpile vaccines to protect against otherpotential attacks. This includes vaccines such as anthrax and small pox.In addition to the terrorist threat, there is also the threat ofpandemic outbreak of diseases such as influenza. At present, thestockpiles of anthrax and small pox vaccines have to be replaced everytwo to three years due to the limited shelf life of the material, evenwhen it is refrigerated. Thus, the ideal vaccine for stockpiling wouldbe stable for many years at room temperature and would not requiretrained healthcare professionals to make the injections in the case ofan emergency. An ideal technology for delivering stockpiled vaccineswould be easy to distribute and easy to use in emergency situations,preferably by non-medical or healthcare personnel.

It is against this background that the Applicant has investigatedalternative solutions to currently available technologies. In addition,current technologies typically do not take into consideration thedifferent requirements demanded by the three main areas of the vaccinemarket. Thus, the Applicant has sought to provide a vaccine formulationand delivery system that overcomes substantially all the problems ofexisting technologies while providing a solution that is suitable foruse in the three main commercial areas.

Accordingly, in its broadest aspect, the invention resides in anelongate body for parenteral injection at low velocity from a device,the body having at least one pointed end and comprising at least oneactive material, characterised in that the body has a compressivestrength of greater than or equal to 5 Newton and the pointed end has anincluded angle of between about 10-50°. The pointed end may have anincluded angle of between about 10-40°.

In another aspect the invention resides in a solid vaccine formulationfor needle-free parenteral delivery, the formulation comprising one ormore antigenic or immunogenic agents. Expressed in another way, thesolid formulation is an elongate body, which may be for parenteralinjection at low velocity from a device. The active may be inter alia avaccine. Where the solid formulation comprises a vaccine, the terms“elongate body” and “solid formulation” are used interchangeably.

An antigenic or immunogenic agent is an agent that is capable ofinducing an immune response within an animal. An alternative term thatis used for such an agent is “antigen” and the two terms will be usedinterchangeably throughout this specification.

The term “solid” is used in the context of a state in which the matteris firm and stable in shape so that the matter retains its own shape. Inparticular, the solid formulation has the shape of a solid rod,splinter, bar or needle.

In a preferred embodiment, the solid formulation has at least onepointed end and a compressive strength of greater than or equal to 5Newton. The pointed end may have an included angle of between about10-50°. A suitable formulation is described in GB Application No.0703507.4 (Glide Pharmaceutical Technologies Limited), the contents ofwhich are incorporated herein by reference.

Ideally the elongate body has a shape and inherent strength to enable itto penetrate unbroken skin.

The term compressive strength refers to the strength of the body whencompressed longitudinally, from end to end, rather thancircumferentially. The Applicant has found that the body must have astrength sufficient for penetration of the skin, such strength typicallyneeding to be greater than or equal to 5 Newton. However, a compressivestrength of between 5 and 500 Newton is suitable for achievingpenetration of the body with a preferred strength being between 5 and 50Newton. A yet further preferred strength is between 5 and 20 Newton andmore preferably approximately 10 Newton. Alternatively, a compressivestrength of between 20 and 50 Newton is preferred with a more preferredstrength being approximately 30 Newton.

In another embodiment, the formulation comprises a pioneer projectile incombination with a solid formulation comprising one or more antigens. Inthis embodiment, the pioneer projectile creates a passage in the skinthat accommodates the solid formulation that follows behind,independently of the pioneer projectile. Such an arrangement isdescribed in WO 03/023773 (Glide Pharmaceutical Technologies Limited),the contents of which are incorporated herein by reference.

The body or the solid formulation of the invention is provided withinertia, by pushing, so that it strikes the skin at a low velocity. Thisinertia enables the provision of a material with a lower compressivestrength and provides improved delivery of the body to the desiredparenteral location. A velocity of between 0.5 and 50 m/s is preferred,more preferably between 0.5 and 20 m/s, optimally between 0.5 and 10m/s.

The body will typically have one pointed end with the other end notbeing pointed. For example, a body may have one flat end and one pointedend, where the pointed end assists the penetration of the target tissue.In an alternative embodiment, the body may have a point on both ends.The Applicant has found that such an embodiment will make the cuttingprocess easier and also facilitates the packaging of the body sincespecific orientation in the packaging will not be required.

The Applicant has found that the geometry of the pointed end has abearing on the force required for penetration of the body: the moreacute the angle of the end, the lower the force required to push thebody into the target tissue. However, if the angle is too acute then itis difficult to manufacture a good pointed end repeatedly. Therefore apreferred included angle of the pointed end is 20-30° and an angle ofabout 23° has been found to be optimal. The included angle is the angleincluded by opposing convergent faces of the pointed end, e.g. acrossthe diameter of a cone, or opposing convergent faces of an end withsquare cross-section or a wedge. Where the end has more than a pair ofdifferent opposing faces, e.g. with an elliptical cross-section, orwhere it tapers with a rectangular cross-section, it is the smallestangle included by two opposing faces. The pointed end may comprise acentral ‘chisel’ tip. The chisel tip may have an included angle ofbetween about 10-50° or 10-40°. In one embodiment, the preferred anglefor an oblique cut of the end is about 23 degrees; the end wouldtherefore have an included angle of 46 degrees according to ourdefinition.

The pointed end has a tip that may be flat, conical, part spheroidal,sphenoidal, or fractured. While a tip ending in a sharp point is ideal,in some instances some shaping or blunting of the tip is desired orinevitable as part of the manufacturing process.

Depending on the chemical structure of the active material and themethod used to make the body, the body may be at least partlycrystalline or at least partly amorphous or glassy.

The active material in the body may selected from the group comprisingpeptides, proteins, DNA, RNA small molecules, labelled molecules, dyes,antigens, vaccines and whole cell vaccines. Small molecules may benaturally occurring or synthetic and may be organic or inorganic. Itwill be understood that the labelled molecules may be labelled with anysuitable label, including a radioactive or chemical label. Such labelledmolecules, as well as dyes, may be used for diagnostic purposes.

In a preferred embodiment, the active material is a pharmaceuticallyactive compound and may be any sort of drug or vaccine, or may be acombination of one or more drugs or vaccines. In the case of somepharmaceutical active materials, such as vaccines, an antigen orantigens may be combined with, or adsorbed to, an adjuvant.

In particular, the pharmaceutically active compound may be used in thetreatment of diseases in the fields of endocrinology, oncology,cardiology, infections, dermatology, obstetrics, gynaecology,respiratory, immunology, treatment of hormonal deficiencies, CNSdisease, emergency medicines, vaccinations, pain control or diabetes.Such treatment includes prophylaxis and preventative treatment.

The or each antigen may be adsorbed onto the surface of the body, orcontained within or as part of the body.

The solid formulation may further comprise one or more adjuvants. Inthis embodiment, the or each antigen may be combined with, or adsorbedto, an adjuvant. Suitable adjuvants include aluminium hydroxide andaluminium phosphate. Other adjuvants that have been incorporated inproducts or are in development include squalene, MF59 (proprietary toNovartis), polymer microspheres and oils.

The solid formulation of the invention may be used to inject one or moredoses simultaneously in a solid dosage form. Alternatively, theinvention allows for the injection of one or more formulationssimultaneously. This provides the opportunity for simultaneousadministration of a quick dissolving formulation and a slower dissolvingor pulsed formulation. In this way, both a prime and boostadministration may be given at the same time. The formulations mayinclude an immediate release formulation and/or a controlled releaseformulation. The formulations may include a continuous releaseformulation and/or a pulsed release formulation.

Having the vaccine in a solid dosage form with enhanced stability isimportant if the antigen is to remain viable in the tissue for a numberof days or weeks. The ability to immunise patients fully with oneinjection will not only save time and money by only treating the patientonce, but it will also ensure that the patient is fully immunised.

Adjuvants are thought to cause a local ‘irritation’ in the skin, therebycausing an enhanced immune response. A solid dosage readily causes localirritation in the skin and this effect could be used in addition to theinclusion of any adjuvants that form part of the initial dosage form.Expressed in another way, a sugar based formulation may have an initialadjuvant effect. Rapid dissolving of the sugar leaves other adjuvantparticles in the tissue creating a longer lasting and/or secondaryirritation. Thus, the solid dosage may elicit a sufficient adjuvanteffect to avoid the need for adjuvant particles to be included in theformulation. Alternatively, the solid dosage may elicit a sufficientadjuvant effect so that the dose of adjuvant particles added to theformulation may be reduced. If reduced levels of adjuvant particles areused within the formulation, costs may be saved on the adjuvant and,more importantly, such a formulation places less foreign material in thehuman, animal or bird that is injected. This is important becauseadjuvants like aluminium hydroxide do not dissolve in tissue.

A solid dosage form also provides the option of a controlled releaseformulation. In this way, the immunogenicity of the vaccination may beincreased, either by slow continuous release of antigen over time and/orpulsed release of some of the antigen at a predetermined time after theinjection. The pulsed release may be achieved automatically by theformulation in the tissue e.g. a slow dissolving coating around a quickdissolving, antigen containing core, so that the antigen is released asa bolus when the outer coating dissolves. Alternatively, pulsed releaseof the antigen may be triggered by an external stimulus at the time theantigen is to be released.

Alternatively, the solid formulation may dissolve rapidly, providing aconcentrated volume of antigen. This high concentration may have aneffect on the immunogenicity of the vaccination.

Producing the vaccines in a solid dosage form means that a number ofantigens may be formulated together. Multivalent vaccines are alreadyproduced but they require significant trials to ensure the individualantigens do not react with each other when in contact in solution. Thisis overcome with solid dose formulations as antigens are far less likelyto react with each other when in a solid state.

A further advantage of a solid formulation is that the optimum immuneresponse may not be found in the standard areas of tissue that aretargeted by a needle and syringe injection. Thus, a solid formulationallows administration of an antigen to tissues and areas that provide ahigher and more efficient immune response, such as the skin. Thus, in apreferred embodiment, the formulation is suitable for dermal,intradermal, transdermal, subcutaneous or intramuscular administration.

A yet further advantage of a solid formulation is that a lower dose ofantigen may be required to achieve a suitable immune response whencompared to a needle and syringe formulation. Expressed in another way,the formulation may produce an enhanced immune response. In other words,an increase in the efficiency of vaccination seen with a solidformulation when compared to a liquid formulation administered vianeedle and syringe. Alternatively or in addition, the dermal,intradermal, transdermal, subcutaneous or intramuscular administrationof the formulation may produce an enhanced immune response. This meansthat either a higher antibody titre could be achieved for the same doseof antigen or alternatively a lower dose of antigen could be used. Inthis way, a solid formulation provides an opportunity for dose sparingwhich, in turn, has an impact on the cost of the vaccine material. Thisalso means that more doses may be obtained from a batch of vaccinematerial. This is particularly important in scenarios such as a pandemicinfluenza outbreak where demand for a vaccine will far outstrip theavailable supply.

Even a ten percent reduction of antigen in each injection would providecost savings but greater efficacy with a solid formulation may lead toonly 75%, 50% or 25% of the antigen required compared to a standardliquid, injection with a needle and syringe. However, antigen doses donot typically show a linear dose response in humans and other animals.Therefore, if a formulation or mode of delivery results in an enhancedimmune response, when compared to a needle and syringe injection, thenonly one tenth, or one hundredth or even one thousandth of the dose ofantigen typically required for needle and syringe administration may berequired to produce the same or an enhanced immune response.

If the antigen dose can be reduced then the dose of adjuvant, ifrequired, may also be reduced to 75%, 50% or 25% of the adjuvantrequired compared to a standard liquid injection with a needle andsyringe. However, if the adjuvant produces a non-linear dose responsethen a solid dose formulation might only require one tenth, or onehundredth or even one thousandth of the dose of adjuvant to give thesame immune response as a needle and syringe.

It will be appreciated that the antigen may be in any suitable form,such as killed, attenuated or combined micro-organisms, inactivatedtoxic compounds, whole or fragments of proteins or polysaccharides, DNAor RNA. The antigen may also be a virosome, a virus-like particle (VLP),complexed or uncomplexed DNA, adeno-associated virus, an alphavirusvector, an adenovirus vector or a poxvirus vector.

The vaccine may be used in the treatment of diseases in the particularfields of oncology, infections, immunology, emergency medicines andvaccinations. Such treatment includes prophylaxis and preventativetreatment.

While the quantity of active material or antigen will be determined bythe dose required, the active material may be present in an amount ofbetween 0.1% and 99.9% by weight of the body, preferably between 0.1 and60% by weight and most preferably in an amount of between 0.1 and 35% byweight. If an adjuvant is desired or required in order to improve theefficacy of the vaccine then this may be present in an amount between0.5% and 99.9% by weight of the body, preferably between 0.5% and 60% byweight and most preferably in an amount between 0.5% and 35% by weight.

The active material may include, or may be included within, an immediaterelease formulation and/or a controlled release formulation. The activematerial may include, or may be included within, a continuous releaseformulation and/or a pulsed release formulation.

In another embodiment, the body further comprises one or moreexcipients. The excipients are typically required to bulk up the activematerial, as well as act as a binder to provide a robust dosage suitablefor administration. In some cases, the active material may be able toact as the binder and bulking agent, meaning that the body may comprise100% active material. In some cases, the antigen may be able to act asthe binder and bulking agent, meaning that the body may comprise 100%antigen. Where low doses of active material are required, higherproportions of excipients may be used. Ideally, any excipients are GRAS(Generally Regarded As Safe) registered for pharmaceutical use,especially parenteral administration.

A variety of excipients may be used but different excipients havedifferent physical properties and act as binders in different ways.Excipients that are typically used in tablet formulations are often thebest binding agents although, if possible, excipients are selected thatare already used in parenteral pharmaceutical products. Excipients maybe selected to give an immediate release of the active to the systemiccirculation or may be selected to provide a sustained or controlledrelease. If immediate release is required, a highly water solubleexcipient or excipients may be used e.g. sugars, polyvinyl pyrrolidone(PVP), polyethylene glycol (PEG). In contrast, if sustained orcontrolled release of the active material is desired then materials suchas biodegradable polymers may be used as the excipients. The phrase“controlled release” refers to formulations where release of the activematerial includes slow or pulsed release, as well as mixtures of slowand fast release. Such formulations may be for prophylactic orpreventative use, as well as therapeutic use.

Disintegrants may also be added, if desired, to assist in thedisintegration of the active material. For example, water solubledisintegrants such as celluloses, including sodium carboxy methylcellulose or PVP or cross-povidone (CPVP), may be used.

As well as providing the physical strength for the formulation, theexcipients may also need to provide any chemical stability required bythe active material or antigen. Such excipients may enable the finaldosages to be stored at room temperature or higher temperatures ratherthan requiring cold chain storage. These excipients may also provide anincreased shelf life and/or protect the active material or antigenthrough processes, such as ionizing radiation or other forms ofsterilization, to ensure that the final dosage is sterile. Examples ofstabilising agents include trahalose, histadine, citrates, lactates,amino acids, polyethers and disodium edetate. Drugs and vaccines aretypically more stable when stored in a solid dosage form and manycurrent drugs and vaccines are stored as lyophilised powders andreconstituted prior to injection with a needle and syringe. While theantigenic or immunogenic agents may need to be lyophilised before beingformulated into a solid formulation, it is the solid formulation that isthen administered. No reconstitution is required and the solidformulation imparts a longer shelf-life to the vaccine. The furtherconsideration with lyophilised powders and stability is that a powderhas a relatively large surface area. In contrast, the solid formulationof the present invention presents a lower surface area to the atmospherecompared to a powder and so should show improved stability andshelf-life.

Accordingly, the excipients may be selected from the group comprisingbulking agents, anti-oxidants such as Vitamin C and metabisulphites,disintegrants, binders, biodegradable polymers, salts and buffers,wetting agents such as poloxamers and polyvinyl alcohol (PVA), adjuvantsand stabilising agents.

Typical materials that may be used as excipients include sugars andcarbohydrates such as mannitol, lactose, sorbitol, sucrose, fructose,trahalose, rafinose, maltose, glucose, dextrose, dextrans,cyclodextrins, maltodextrins and sodium alginate. Some of thesematerials may act as binders and/or bulking agents and/or stabilisersdepending on the active material. Sugar based formulations typicallyproduce very fast dissolving formulations. Sorbitol is a preferredexcipient as it acts as both a binder and a filler/bulking agent and isapproved for parenteral administration. Alternative bulking agents maybe alkali metal salts, including sodium and magnesium, lactate, citrate,tartrate and gluconate. An alternative binder may be PVP. Sodiumalginate has also been used as an excipient to produce robustformulations. The excipient may therefore be sodium alginate.

Stabilizers may be added to increase the shelf life of the product andavoid refrigeration. Also, stabilizers may be added to protect thedrug/vaccine from ionizing radiation during sterilization. The body maycomprise a stabilising excipient which performs each of these functions,or the body may comprise two or more stabilising excipients, eachperforming one of these functions.

Suitable salts and buffers include citric acid and sodium citrate,tartaric acid and sodium tartrate, lactic acid and sodium lactate, andmaleic acid and sodium maleate.

Other materials that may be used include polyethers, such aspolyethylene glycol; polyethers are particularly suitable for quickdissolving formulations. It will be appreciated that polyethers shouldhave a molecular weight above 1000 kDa because, below this molecularweight, the compounds are liquid at room temperature.

If a slower release of the active material to the systemic circulationis required, biodegradable polymer materials may be incorporated. Thepolymer, such as polylactide-co-glycolide (PLG), poly(lactic-co-glycolic) acid (PLGA), polycaprolactone, polyanhydride andpolyorthoesters, may be incorporated as microspheres in a fastdissolving matrix. Alternatively, the polymer may be used as the mainbulking agent or binder in the formulation.

It may also be desired to coat a fast dissolving formulation with aslower dissolving material so that the active material within the fastdissolving formulation is released to the systemic circulation hours,days, weeks or months after the administration of the body of theinvention to the target tissue.

Preferably, the active material is homogeneously dispersed throughoutthe body. However, the body may have an inert pointed end or tip withthe active material being found in the elongate part of the body. Insuch an embodiment, the active material may separated from thenon-active material in the body by any suitable means.

Alternatively, the antigen may be sprayed onto the outside of the bodywhich therefore acts as a carrier. Preferably, the antigen ishomogeneously dispersed throughout the body. However, the body may havean inert pointed end or tip with the antigen being found in the elongatepart of the body. In such an embodiment, the antigen may be separatedfrom the non-active material in the body by any suitable means.

Advantageously, the elongate body has a diameter of between about 0.5 mmand 3 mm, although an ideal diameter is between about 0.6 mm and 1.5 mm.The body may have a length of a few millimeters up to about 15 mm,although a length of 2-8 mm is preferred.

It will be appreciated that the body may be of any suitablecross-sectional shape, including ovoid, triangular, circular, obround (aclosed figure having two parallel sides and two semi-circular ends),rectangular and polygonal.

In another aspect, the invention resides in a method for making theelongate body of the invention. The method comprises:

-   -   i) mixing the at least one active material and any excipients as        dry material with a fluid to produce a paste;    -   ii) forming the paste;    -   iii) cutting the paste to a shape having at least one pointed        end with an included angle of between about 10-50°, the method        further comprising drying the paste either before or after the        cutting step.

In particular, the method comprises i) mixing the at least one activematerial and any excipients as dry material with a fluid to produce apaste; ii) forming the paste; iii) drying the paste; and iv) cutting thepaste to a shape having at least one pointed end with an included angleof between about 10-50°.

The method may comprise i) mixing the at least one active material andany excipients as dry material with a fluid to produce a paste; ii)forming the paste; iii) cutting the paste to a shape having at least onepointed end with an included angle of between about 10-50°; and iv)drying the paste.

The included angle may be between about 10-40°.

In one embodiment, any excipients may be mixed into a dry homogenous mixbefore being added to the active material and fluid. Alternatively, someor all of the active material and some or all of one or more excipientsmay be added to the fluid before mixing with the remaining dry material.One advantage of adding the active material to the fluid, is that it ispossible to achieve very good mixing of the active material throughoutthe formulation. In yet another alternative, some or all of one or moreexcipients may be added to the fluid before being mixed with the activematerial and any remaining dry material.

In a further embodiment, a dry mix of the active material and anyexcipients may be prepared before addition to the fluid if the activematerial cannot be dissolved or incorporated in a small enough quantityof fluid. In this embodiment, the active material is ideally mixed withan approximately equal quantity of the excipients and mixed thoroughlybefore adding another equal quantity of excipients and mixing until allthe excipients are used. The excipients are preferably added in smallquantities to ensure good mixing. Once a homogenous mixture has beencreated, the fluid is preferably added to the dry material and theresultant mixture formed.

Another advantage of this process is that the method can be undertakenat or below room temperature. Elevated temperatures, even for shortperiods of time, can cause degradation of proteins and peptides. Thus, atemperature of above 4° C., preferably ambient temperature isadvantageous, with an optimal temperature being between 18° C. and 22°C.

The Applicant has found that the addition of a fluid to the drymaterials lubricates the mixture and makes formation easier and morereliable and significantly increases output from the process. The fluidis, in essence, a granulation fluid as it granulates the dry materials.While the preferred granulation fluid is water, any other fluid can beused that does not damage the formulation and will allow theformulations to dry (i.e. not oils). The granulation fluid is preferablya slimy and might be an alcohol, solvent or other buffered solution. Inthis context, a buffered solution is a solution that contains salts orchemicals. Such salts or chemicals typically act to stabilise the activematerial.

An important aspect of the process is the quantity of granulation fluidthat is added to the dry material to ensure that the formed material isneither too dry as a ‘shark skin’ rather than smooth appearance) or toowet (cannot hold its shape under its own weight). Thus, the fluid ispreferably added to the dry material in an amount of less than or equalto 10-30% volume by weight, ideally approximately 15% volume by weightof the dry material.

Particle size can make a difference to strength of the formulations. Theat least one active material and/or and any excipients may be in theform of particles. The particles may be of a standard or uniform size,for example a standard or uniform diameter, or longest dimension. Suchstandardised particles may provide better strength for the elongate bodyof the invention.

In another embodiment, the method additionally includes grinding the drymaterial.

A particle size of from 0.1-1000 micrometers in diameter isadvantageous, while a particle size is less than 500 micrometers indiameter is preferred and a particle size is less than 300 micrometersin diameter is still further preferred.

The method may therefore include either starting withactive(s)/excipient(s) in particulate form, or grinding same intoparticles.

In some cases, it might be desirable to use higher temperatures for theformation of the body. Therefore, the method may further includesoftening or melting the paste either before or after the paste isformed. The temperature of the paste is raised such that at least one ofthe excipients or the active material softens or melts and, as it cools,it hardens and acts as a binder. A drawback of raising the temperatureof the paste is that the active material is necessarily heated which maycause some degradation of the active material. In addition, thematerials either need to be mixed thoroughly in the solid form prior tothe partial melting, which means that a homogenous mixture is moredifficult to achieve, or the materials are mixed in a molten orpartially melted form requiring the materials to be kept at a highertemperature for a longer period of time.

However, the Applicant has found that, in some instances, raising thetemperature to soften or melt the mixture is desired and even preferred.The softened or melted material is in a pasty condition for furtherforming. Accordingly, in a yet further embodiment, the invention alsoresides in a method for making the elongate body of the invention, themethod comprising i) mixing the at least one active material and anyexcipients in a dry form to produce a dry mixture; ii) softening ormelting the mixture; iii) forming the mixture; iv) cooling the mixture;and v) optionally cutting the mixture to a shape, wherein the mixture isformed or cut to a shape having at least one pointed end with anincluded angle of between about 10-50°. The included angle may bebetween about 10-40°.

This method is particularly suitable where the mixture includes one ormore carbohydrates or polyethers as an excipient. Preferably, theexcipient is one or more polyethers.

Preferably the method is carried out at a temperature of between 30° C.and 150° C., more preferably in a range of 40° C. to 100° C. While thechoice of temperature is partly dependent on the nature of the activematerial and any excipients, a lower temperature is desired therebymitigating any damage to and disintegration of the one or more activematerial.

With either method, the paste or dry mixture may be formed by extrusion,tabletting or injection moulding. Ideally, the paste or dry mixture isformed by extrusion through a die.

However, extrusion has its difficulties and drawbacks and the design ofthe die is also important. For small scale formulation work or whenworking with potent drugs where batch sizes, even at a commercial scale,will be small, the Applicant has found that it is more efficient to usea ram extruder rather than a screw extruder. In particular, it has beenfound that a screw extruder results in relatively large quantities ofmaterial being wasted in the screw. Thus, a ram extruder is preferred toproduce a higher yield.

To assist with extrusion, the die itself may be heated so that all ofthe mixture in the die is in the same physical form before extrusion.Alternatively, the heating elements might be towards the exit of thedie, causing the material on the outside of the mixture to melt orsoften during the extrusion process without affecting the core of theextrudate.

The extruded lengths of material need to be cut before they can beadministered via a drug delivery system. The cutting can be undertakenwith a range of different processes including a blade (hot or cold),ultrasound, a laser or a water jet. The paste may therefore be cut usingcutting means selected from the group consisting of a blade, ultrasound,a laser, and a water jet. The cutting means may be either hot or cold,for example, the laser is likely to be hot. The cutting means may beheated or at room or ambient temperature.

The paste may be cut, for example by using a blade, while the extrudateis still soft. The paste may be cut, for example by using a heatedblade, when the extrudate is dry and solid.

The cutting process used will determine the preferred state for theextrudate. Advantageously the extrudate is cut using a blade. If a sharpcold knife is used then the extrudate is preferably cut while stillsoft. The blade may be like a guillotine or a rotating blade. If aheated blade is used, the extrudate is advantageously cut while thematerial is dry and solid, but may also be used to cut the extrudatewhen in the form of a soft paste. Again, either a guillotine or rotaryblade can be used but the hot blade will cause the material along thecut faces to melt or soften as it cuts.

Ultrasonic cutters are typically used with soft materials and lasers maybe used with either soft or hard materials.

There are alternative manufacturing techniques to extrusion. The firstof these is a standard tabletting process. The main drawback withtabletting is to achieve a consistent fill of material into the tabletpress and then to compress the material consistently without damagingthe tools. It may also prove difficult to produce a tablet that has apoint on one end and if this process is used, the point may have to becut as a separate process.

If a hot melt process is utilized, an alternative process is to mouldthe desired material using a standard injection moulding technique. Inthis case the individual body may be moulded with a pointed end, or alonger body may be moulded and then individual bodies cut to size andshape.

In a yet further embodiment, the method further comprises adding one ormore disintegrants or controlled release agents to the active materialor dry mixture.

In a still further alternative, the body may have an inert pointed endwith the elongate part of the body comprising the active material.Accordingly, the pointed end may be moulded and the subsequent pieces ofbody comprising the at least one active material might be separatelymoulded, tabletted, extruded, spray dried or using any other standardmanufacturing process.

The formulation of the invention or the body of the invention, when madeby either method, is preferably provided with a packaging, such as acap, cartridge, carousel or cassette. While standard packaging may beused, it is advantageous if the body is packaged with the packaging setout in WO 2004/014468, the full content of which is incorporated herein.

In particular, the packaging comprises a) a housing having a channelrunning there through and in which is disposed a drive pin or otherelement, and b) the formulation or body of the present invention. Theformulation or body is disposed distal to the drive pin. The housingcomprises i) a region allowing the packaged vaccine to be slidablymounted to a suitable delivery device; and ii) an end adapted to engageand tension the skin.

In the following description, the phrase ‘packaged vaccine’ can be takento mean ‘packaged drug’, and vice versa. Preferably the packaged vaccineor drug takes the form of a disposable end cap, cartridge, cassette orcarousel, containing a single or multiple doses of the vaccine.

Advantageously, the region for engaging the packaged vaccine or drug tothe delivery device in a slidable manner additionally comprises a meansfor positively locking it to the device such that housing is able toslide within the device but not fall out under gravity. Such a meansmight be a sprung pin or spigot which exerts a frictional force againstthe device or a mechanism whereby the packaged vaccine or drug isinserted in a particular orientation and turned so that it is precludedfrom being removed unless it is turned back into the position in whichit was allowed to enter.

In one embodiment, the drive pin or element may have a plurality offlexible or frangible arms extending from its main body. These armsextend outwards (splay) when they ride over a ramped surface provided onthe housing, are forced away from the body, and ride over a lip on thehousing as a consequence of the flex or frangibility. Where the arms arefrangible, the arms will snap off as a result of an area of weaknessformed about the shoulder region and fall into a cavity about the rampedregion. A frangible system has two advantages: firstly it should ensurefull injection occurs, and secondly it will prevent the packaged vaccineor drug from being re-used. The ramp is preferably circular in design,taking the form of a frustoconical surface. This has the advantage thatit can be easily moulded and does not require the arms to be orientatedfor contact.

The packaged vaccine or drug may be sealed in a foil pouch or the liketo prevent ingress of, for example, moisture, oxygen, light, bacteria orother vaccine or drug degrading or contaminating agents.

Preferably the end of the packaging adapted to engage and tension theskin comprises one or more projections about the channel exit, mostpreferably in the form of an annular ring, as such an arrangement mosteffectively tensions the skin.

A retention system may advantageously be employed to hold theformulation or body of the invention in place in the channel. This mightbe achieved by, for example, extruding or moulding the body with anumber of small splines or other features on its outer surface. Thesesplines or other features should provide a frictional fit withoutprohibiting the vaccine or drug from being administered. Alternatively,the channel of the packaging might have a small feature, such as aretaining bump or other projection, over which the formulation or bodymust be pushed.

A tamper or use evident seal or other indicator means may additionallybe placed over the top end of the packaged vaccine or drug so it isapparent to the user that the packaged vaccine or drug has not beeninterfered with and/or is spent.

Additionally or alternatively, a seal may be placed over the exit of thechannel of the packaged vaccine or drug. It is preferable to remove thisseal prior to administration of the vaccine or drug but, ideally, theseal should be designed such that administration may be carried outthrough the seal in case the seal is accidentally left on the packagingduring administration.

Suitable delivery devices are also described in GB Application No.0703507.4 and WO 03/023773, as well as WO 2004/014468 and WO2006/082439, the contents of which are incorporated herein by reference.Suitable solid therapeutic formulations are propelled at low velocityfrom a needleless device, known as the Glide SDI™ (Solid Dose Injector).

The Glide SDI™ injects the antigen or drug in a solid dosage formthrough the skin and does not require a needle. The technology comprisesa small, single use, disposable cassette that contains the vaccine ordrug and a reusable, spring powered actuator.

The Glide SDI™ comprises a small, low cost, disposable cassette carryingthe vaccine or drug formulation that is used once and then thrown away.The actuator may be used hundreds of times and is spring powered. Thevaccine or drug for the Glide SDI™ may be stored in a solid dosage formand therefore is expected to be more stable than a standard liquidvaccine or drug. This offers the potential for a longer shelf life oreven to avoid cold chain storage. The Glide SDI™ is very easy to use anddoes not require a trained healthcare professional for use. This mightbe particularly important in the case of a pandemic or a terroristattack. Needle phobia is not a major issue in developing countries andis not likely to be an issue in the case of a pandemic. Very few peoplelike needles and therefore a needle-free system will help compliancerates in industrialised nations, especially amongst children. The GlideSDI™ makes a pin-point mark on the skin, the same as is left followingan injection with a needle and syringe, and so causes no adverseeffects. The Glide SDI™ does not require a needle and therefore thereare none of the dangers associated with needle-stick injuries, needlereuse and cross-contamination. The Glide SDI™ has a small, light-weight,disposable cassette carrying the vaccine or drug formulation which meansthe vaccine or drug is easier and lighter to transport than a liquidvaccine or drug in a glass vial and so will be quick to distribute. Thisis particularly important in the case of emergencies, a terrorist attackor a pandemic outbreak.

In this way, the present invention addresses all of the key featurescost, stability, ease of use, needle phobia, adverse effects,cross-contamination and quick distribution. Equally, the presentinvention provides a solution that is suitable for use in all threeareas of the vaccine industry as well as for the injection of drugs inboth a home environment or in a healthcare setting.

The Glide SDI™ injects the vaccines and drugs through the skin. Thus,the antigen or drug may be injected into the muscle or subcutaneoustissue. Alternatively, and particularly in, the case of vaccines, someof the antigen may be left in the dermis, making best use of theimmunological properties of the skin. This may be achieved by injectingthe solid dose parallel with the skin (by taking a pinch in the skinprior to the injection) and/or by leaving the trailing end of theformulation level with the skin surface.

The Glide SDI™ injects vaccines in a solid dosage form making it easyfor adjuvants such as alum, gold particles or PLGA particles to be usedin the formulations. If the adjuvant particles need to be injected witha needle and syringe, this limits the size of particles to avoidclogging of the needle.

Thus, in a yet further aspect, the invention resides in a drug deliverydevice comprising a packaged vaccine or drug as set out above. While anysuitable drug delivery device may be used, it is preferred that thedevice is as set out and described in WO 2004/014468, the full contentsof which are incorporated herein. The device comprises i) a housing; ii)means for generating a force capable of pushing the formulation from thepackaging into a human, animal or avian body; iii) means fortransmitting the force to push the formulation from the packaging intothe human, animal or avian body; and iv) means for triggering thedevice.

Such a device may be a reusable device which further comprises means forreceiving the packaged vaccine or drug of the invention and means forpriming the device.

Alternatively the device may be a single use device in which case thepackaged vaccine or drug might be an integral part of the device. Such adevice can be provided in a pre-primed form which simply requirestriggering, or in a form requiring it to be primed.

In a preferred embodiment, the device may only be actuated by insertingthe packaged vaccine or drug and pushing a skin tensioning end of thepackaged vaccine or drug against a solid object. The priming andactuation of the device by pushing the end of the device against theskin ensures that there is a reliable and consistent contact andtensioning of the skin on delivery of the vaccine or drug. Additionally,by setting the device so that the force required to actuate it is from,for example, 10-30 Newton, the force will be too high for a patient toactuate the device accidentally without pushing it firmly against thebody's tensioned skin, thereby providing a significant safety feature.

The addition of a spring and cap arrangement makes it possible to adjustthe actuation force by altering the tension on the spring. By screwingthe cap further onto an upper barrel of the device, the spring istensioned and, by unscrewing it, the force can be reduced.Alternatively, instead of a coil spring as the main power source, thedevice could incorporate any other type of mechanical spring or a gasspring. In an alternative embodiment the spring could be pre-tensionedduring manufacture to avoid having to tension the spring during thevaccine or drug administration. This would result in a single use devicein which, as mentioned above, the packaged vaccine or drug would mostlikely be an integral part of the device.

The velocity of an impact hammer within the device during administrationof the formulation is less than 50 m/s, more preferably less than 20m/s, more preferably still less than 10 m/s. The skilled person willappreciate that the actual speed may vary with the mass of the impacthammer and thus the impact imparted on the formulation. As a consequencethe body is delivered by a pushing action from the end of the packagedvaccine or drug rather than by a firing action (as would be the casewith a bullet leaving the barrel of a gun).

To ensure that the device actuates automatically when the correct forceis applied, the hammer may include a shaped shoulder region whichengages a correspondingly shaped surface in a wall separating upper andlower barrels of the device. Such a device will actuate only when thesubstantially frustoconical sections fully engage. This will be at thesame main spring tension every administration and, if the administrationis aborted before the frustoconical sections engage, the packagedvaccine or drug can be removed safely without leaving the device primed.

In a preferred embodiment, the device cannot be primed until thepackaged vaccine or drug is attached thereto since it is the packagedvaccine or drug that acts against a piston in the device to cause thespring to be tensioned. This makes the device particularly safe. It alsomeans the device cannot be actuated unless and until it is loaded suchthat an operator is not able to use the device in a belief they areproviding an injection.

In the case of a reusable device, a slewing spring may be used to returnthe impact hammer into its non axially aligned position at the end ofeach administration.

Furthermore, because the reusable components of the system (allcomponents except those of the packaged vaccine or drug) do not comeinto contact with the target tissue for administration of the vaccine,they do need to be sterile.

All components, apart from any springs, are preferably moulded makingthe device cheap to manufacture. The limited number of parts and theirease of assembly keeps manufacturing costs to a minimum.

From another aspect, the present invention encompasses use of the soliddose formulation described above in the preparation of a medicament forthe treatment of an infection with a pathogen or a tumour cell.

Alternatively, the present invention encompasses use of the solid doseformulation described above in the preparation of a medicament toenhance an immune response to one or more antigens, or antigenic orimmunological agents.

Ideally, the use of the medicament is prophylactic to reduce thelikelihood of infection. Alternatively, the use may be curative,post-infection.

In a preferred embodiment, the medicament is for dermal, intradermal,transdermal, subcutaneous or intramuscular administration.

Ideally, the formulation enhances the immunogenicity of the one or moreantigens. Alternatively, the dermal, intradermal, transdermal,subcutaneous or intramuscular administration enhances the immunogenicityof the one or more antigens.

From a yet further aspect, the present invention resides in a method ofvaccination of a vertebrate, such as mammal or bird, from infection witha pathogen or a tumour cell. The method comprises administering animmunogenically or antigenically effective amount of a solid formulationcomprising one or more antigenic or immunogenic agents.

Expressed in another way, the invention resides in a method foreliciting an enhanced immune response from an antigenic or immunogenicagent in a vertebrate, the method comprising dermal, intradermal,transdermal, subcutaneous or intramuscular administration of a solidvaccine composition, wherein the solid vaccine composition comprises aneffective amount of one or more antigenic or immunogenic agents.

As described above, an effective amount of antigenic or immunogenicagent could be 75%, 50% or 25% by weight of the dose required for aliquid formulation injected with a needle and syringe. In other words,the effective amount of antigenic or immunogenic agent might be onetenth of one hundredth or even one thousandth of the dose required for aliquid formulation injected with a needle and syringe.

A reduction in the amount of antigenic or immunogenic agent in the solidformulation might also lead to an equivalent reduction in the amount ofadjuvant required in the formulation. A solid formulation, in itself,might act as an adjuvant in the skin thus allowing a further reductionin the dose of adjuvant particles that might be added to the solidformulation.

From another angle, the invention relates to a method of enhancingdirect or subsequent immunological responses to one or more antigens ina vaccine formulation, the method comprising administering the one ormore antigens in a solid formulation.

Alternatively, the present invention is directed to a method forenhancing the immunogenicity of one or more antigens, the methodcomprising administering an effective amount of the one or more antigensin a solid formulation through the skin, subcutaneous layer or muscle ofa vertebrate, such as a mammal or bird.

In a yet further alternative, the method encompasses a method ofpromoting highly efficient antigen presentation in a vertebrate, such asa mammal or bird, comprising exposing the vertebrate to a solidformulation of the antigen.

Advantageously, the solid composition or formulation is formulated in aformulation as described above.

Ideally, the formulation is administered dermally, intradermally,transdermally, subcutaneously or intramuscularly. The Applicant hasfound that administration of the formulation in a plane parallel to thesurface of the kin is effective.

It is advantageous if administration is by way of a needle-free deliverysystem. Preferably, the delivery system administers the formulationusing a low velocity, pushing force. The velocity may be less than 50m/s, preferably less than 20 m/s and more preferably less than 10 m/s.

Aspects of the present invention will now be described further by way ofnon-limiting examples, in which:

FIG. 1 shows anti-diphtheria IgG titres after first and second boosts ofnon-adsorbed diphtheria toxoid. Subcutaneous needle and syringeadministration, Glide SDI™ administration and subcutaneousadministration of reconstituted SDI™ solid formulation were compared.Clear bars represent the first boost; grey bars represent the secondboost.

FIG. 2 shows anti-DTx neutralising antibody titres after first andsecond boosts of non-adsorbed diphtheria toxoid. Subcutaneous needle andsyringe administration, Glide SDI™ administration and subcutaneousadministration of reconstituted SDI™ solid formulation were compared.The clear boxes represent the first boost while grey boxes represent thesecond boost.

FIG. 3 shows anti-diphtheria antibody titres measured by ELISA over acourse of fourteen weeks, with a boost given four weeks after the primeadministration of adsorbed diphtheria vaccine. Square symbols representthe needle and syringe subcutaneous administration. The triangle symbolsrepresent administration by Glide SDI™.

FIG. 4 shows anti-diphtheria toxin neutralizing antibody in IU/ml afteradministration of adsorbed diphtheria vaccine expressed against areference guinea pig serum calibrated in IU/ml. Square symbols representthe needle and syringe subcutaneous administration. The triangle symbolsrepresent administration by Glide SDI™.

FIG. 5 shows anti-PRP antibody titres two weeks after a first boost (redbars) and two weeks after a second boost (blue bars) of Haemophilusinfluenzae type b (Hib) vaccine administered via needle and syringe orGlide SDI™. The anti-PRP IgG titre is a log scale. A titre of 10 for thesubcutaneous arm is the lower limit of detection for the assay andindicates no measurable response.

EXAMPLE 1

The data provided below suggests that the solid formulation of thepresent invention produces a more consistent and reliable immuneresponse than a standard needle and syringe injection.

A standard diphtheria vaccine without any adjuvant was formulated intomaterial suitable for delivery with the Glide SDI™. A formulation withapproximately 2 Lf per dosage was used in a guinea pig model. Theexcipient used for these solid formulations was sorbitol. The followinggroups were compared:

-   -   1. Standard needle and syringe;    -   2. Glide SDI™; and    -   3. Glide SDI™ formulation reconstituted and injected through a        needle and syringe.

The animals had a prime injection with boost injections after four andeight weeks. Two weeks after each boost blood samples produced theanti-diphtheria antibody titres shown in FIG. 1. For the Anti-diphtheriaIgG ELISA the results are expressed as anti-diphtheria IgG antibodies inInternational Units per ml (IU/ml) against a reference guinea pig serumcalibrated in IU/ml. Limit of detection=0.001 IU/ml

Functional toxin-neutralising antibody measurements were made using avero cell assay. Results are shown in the FIG. 2 where anti-diphtheriatoxin neutralizing antibody in IU/ml is expressed against a referenceguinea pig serum calibrated in IU/ml. Limit of detection=0.0075 IU/ml.

There is no significant difference in the results seen with the threecohorts above although it is thought that the responses in this animalmodel are possibly maximised in this study. It can be seen with Example3 below that when antigen dosing is reduced, a difference in efficacy isseen between standard needle and syringe administration compared to asolid dosage form.

EXAMPLE 2

An adjuvanted diphtheria vaccine was formulated into material suitablefor delivery with the Glide SDI™. The adjuvant was aluminium hydroxide(alum) and the excipient was sorbitol. A formulation with approximately2 IU (approximately 0.9 Lf) per dosage was used in a guinea pig model.The following groups were compared:

-   -   1. Standard needle and syringe; and    -   2. Glide SDI™.

The animals had a prime injection with a single boost injection afterfour weeks. Blood samples were taken two weeks after the prime injectionand at two, six and twelve weeks after the boost injection. Theanti-diphtheria antibody titres measured are shown in FIG. 3. These dataare measured in the same manner as for Example 1.

Functional toxin-neutralising antibody measurements were made using avero cell assay, as outlined in Example 1. The results shown in FIG. 4are expressed as anti-diphtheria toxin neutralizing antibody in againsta reference guinea pig serum calibrated in IU/ml.

It can be seen that there is no significant difference between the meanresults for the two delivery techniques. However, the variability ofresponse to immunisation is lower in the group immunised with the GlideSDI™. It is of note that the kinetics of the antibody responsepost-boost differs between total antibody titres and functionalneutralising antibody titres. While total antibody levels remainconstant or fall slightly in the weeks post boost, functional antibodylevels are higher 12 weeks after boost compared to those measured 2weeks after boost.

EXAMPLE 3

A standard Haemophilus influenzae type b (Hib) vaccine (which does notcontain an adjuvant) was formulated into material suitable for deliverywith the Glide SDI™. A formulation with approximately 1/40 of a standardhuman dose was used in a guinea pig model. The excipient used wassorbitol. The following groups were compared:

-   -   1. Standard needle and syringe; and    -   2. Glide SDI™.

The animals had a prime injection with boost injections after four andeight weeks. Two weeks after the first boost and two weeks after thesecond boost blood samples produced the anti-PRP antibody titres shownin FIG. 5.

It can be seen that the Glide SDI™ produced a low but measurable immuneresponse two weeks after the first boost and this was further enhancedwith the second boost. The standard needle and syringe injections didnot produce an immune response with this does of Hib in guinea pigs.These data indicate a dose sparing effect compared to a standard needleand syringe injection as well as a more consistent and reliableresponse.

In addition to the measurement of antibody titres a functionalprotection test was undertaken. Infant rats (3-5 days old) were injectedi.p. with 100 μl of pooled immune serum (diluted 1:1 with saline) onday 1. After 24 hours (day 2), the animals were challenged with 1×10⁴CFU of Hib (Eagan strain). After another 24 hr (day 3) animals were bledand triplicates of 10 μl of blood were cultured for the presence of Hibbacteria on chocolate agar blood for 24 hours.

The results showed that the immune sera induced by the Glide SDI Hibdosages induced 100% protection in the infant rat bacteraemia model(10/10 animals had no bacteraemia). Sera from subcutaneous needle andsyringe Hib cohort induced only 50% protection (5/10 animals had nobacteraemia).

These data demonstrate that the Glide SDI produced protective antibodiescompared to the needle and syringe cohort in this study.

EXAMPLE 4

10 grammes of sorbitol powder were mixed with 1.5 ml of water and asmooth dry paste was produced. The paste was added to the barrel of aram extruder and the mixture was extruded through a die with an exithole of 0.9 mm diameter. The resultant extrudate was a smooth rod ofmaterial which was allowed to dry overnight in a desiccant chamber. Thematerial, when as cut with a warm blade and individual dosages wereformed with a flat end on one end and a point on the other end. Thepointed end had an included angle of approximately 23 degrees and alength of approximately 4 mm. Short rods of the same material ofapproximately 6 mm in length were cut with a flat end on both ends.These rods were tested on a force meter for their longitudinal crushstrength which was approximately 10N. The dosages having a pointed endwere successfully injected into pig skin, ex vivo, using the Glidetechnology as described in WO 03/023773 and WO 2004/014468 (developed byGlide Pharma, Abingdon, UK.) demonstrating that this placebo formulationcould be delivered to human tissue, if desired.

EXAMPLE 5

1.8 grammes of sorbitol powder were weighed out. 200 milligrammes offentanyl citrate was added to approx 300 microliters of water andallowed to dissolve. The solution was added to the sorbitol powder andproduced a smooth dry paste. The paste was processed and tested in thesame manner as outlined in Example 1 and no difference was seen in anyof the results. The quantity of fentanyl added to the formulation was atypical adult dose per final dosage. A number of the individual dosageswere assayed for content of fentanyl and very good homogeneity had beenachieved through the mix.

EXAMPLE 6

2 grammes of sumatriptan succinate were mixed with 2 grammes ofpolyethylene glycol. The mix was heated to approximately 70° C. andextruded as a smooth rod through a die with an exit diameter ofapproximately 1.0 mm. On cooling, the extrudate solidified and couldthen be cut into individual lengths and tested as outlined in Example 1.The dosages were successfully delivered to pig skin, ex vivo, using theGlide technology.

EXAMPLE 7

500 mg of sodium alginate was mixed with 500 mg of sumatriptansuccinate. 450 microliters of water was added and a smooth material wasextruded which, when dried, was approximately 0.77 mm in diameter. Shortlengths of this material had a longitudinal crush strength ofapproximately 42N. Sodium alginate can be used as an excipient in lowerconcentrations in formulations which still have sufficient strength topenetrate pig skin, ex vivo, using the Glide Technology.

We claim:
 1. An elongate body for parenteral injection at low velocityfrom a device, the body having a compressive strength between 50 and 500Newton and a pointed end having an included angle of between 10-50°,wherein the body is at least partly crystalline, does not contain acoating, and comprises at least one active material, the at least oneactive material being a peptide, a protein, a DNA, an RNA, a smallmolecule, a labelled molecule, a dye, an antigen, a vaccine, a wholecell vaccine, a killed micro-organism, an attenuated micro-organism, aninactive toxic compound, or a polysaccharide.
 2. An elongate body forparenteral injection at low velocity from a device, the body having acompressive strength between 50 and 500 Newton and at least one pointedend having an included angle of between 10-50°, wherein the body is atleast partly crystalline, does not contain a coating, and comprises atleast one active material, the at least one active material being apeptide, a protein, a DNA, an RNA, a small molecule, a labelledmolecule, a dye, an antigen, a vaccine, a whole cell vaccine, a killedmicro-organism, an attenuated micro-organism, an inactive toxiccompound, or a polysaccharide.
 3. The body of claim 2, wherein the atleast one pointed end has an included angle of between 20-30°.
 4. Thebody of claim 3, wherein the pointed end has an included angle of 23°.5. The body of claim 2, wherein the pointed end has a tip that is flat,conical, part spheroidal, sphenoidal, or fractured.
 6. The body of claim1, wherein the at least one active material is a pharmaceutically activematerial.
 7. The body of claim 1, wherein the active material is presentin an amount of between 0.1% and 99.9% by weight.
 8. The solid vaccineformulation comprising the body of claim 1, the formulation beingparenterally administerable without a needle, the formulation comprisingat least one antigenic or immunogenic agent, and optionally at least oneexcipient.
 9. The vaccine formulation of claim 8, wherein the at leastone antigenic or immunogenic agent is adsorbed onto the surface of thebody.
 10. The vaccine formulation of claim 8, wherein the at least oneantigenic or immunogenic agent is dispersed homogeneously throughout thebody.
 11. The vaccine formulation of claim 8, wherein the body has aninert pointed end, and the at least one antigenic or immunogenic agentis dispersed in the elongate part of the body.
 12. The vaccineformulation of claim 8, wherein the body has an inert pointed end, andthe at least one antigenic or immunogenic agent is adsorbed on theelongate part of the body.
 13. The vaccine formulation of claim 8,further comprising at least one adjuvant.
 14. The vaccine formulation ofclaim 13, wherein the at least one adjuvant is aluminium hydroxide. 15.The vaccine formulation of claim 8, wherein the formulation comprisesmore than one dose of the antigenic or immunogenic agent.
 16. Thevaccine formulation of claim 15, wherein the formulation comprises aprime and at least one boost dose of the antigen.
 17. The vaccineformulation of claim 16, wherein the formulation comprises more than oneboost dose of the antigenic or immunogenic agent.
 18. The vaccineformulation of claim 8, wherein the formulation comprises more than oneformulation of the antigenic or immunogenic agent.
 19. The body of claim1 wherein the active material includes or is included within at leastone of an immediate release formulation, a controlled releaseformulation, a continuous release formulation and a pulsed releaseformulation.
 20. The vaccine formulation of claim 8, wherein theantigenic or immunogenic agent content of the formulation is between0.01% and 100% by weight.
 21. The vaccine formulation of claim 8,wherein the at least one antigenic or immunogenic agent is diphtheriatoxin, a Haemophilus influenzae type b (Hib) antigen or immunogen, or atumor specific antigen.
 22. The vaccine formulation of claim 8, whereinthe excipient is a bulking agent, an anti-oxidant, a disintegrant, abinder, a biodegradable polymer, a salt, a buffer, a wetting agent, anadjuvant, a stabilising agent, a binder, a filler, a chemicalstabilizer, a sugar, a polyether.
 23. The vaccine formulation of claim 8in the form of a dermal, intradermal, transdermal, subcutaneous orintramuscular administerable formulation.
 24. The body of claim 1,wherein the active material is homogeneously dispersed throughout thebody.
 25. The body of claim 2, wherein the at least one pointed end ofthe body contains a non-active material.
 26. The body of claim 25,wherein the active material is separated from the non-active material inthe body.
 27. The body of claim 1, wherein the body has across-sectional shape that is ovoid, triangular, circular, round,rectangular or polygonal.
 28. A package comprising the vaccineformulation of claim
 8. 29. The body of claim 1, wherein the activematerial is present in an amount of between 0.1 and 60% by weight. 30.The body of claim 1, wherein the active material is present in an amountof between 0.1 and 35% by weight.
 31. The vaccine formulation of claim8, wherein the antigenic or immunogenic agent content of the formulationis between 0.01% and 60% by weight.
 32. The vaccine formulation of claim8, wherein the antigenic or immunogenic agent content of the formulationis between 0.01% to 35% by weight.
 33. The vaccine formulation of claim8, wherein the antigenic or immunogenic agent content of the formulationis between 0.5% and 99.9% by weight.
 34. The vaccine formulation ofclaim 8, wherein the antigenic or immunogenic agent content of theformulation is between 0.5% and 60% by weight.
 35. The vaccineformulation of claim 8, wherein the antigenic or immunogenic agentcontent of the formulation is between 0.5% and 35% by weight.